Sex-Specific Metabolic and Epigenetic Programming of Cardiac Differentiation by Developmental Lead Exposure.

发育性铅暴露对心脏分化的性别特异性代谢和表观遗传编程。

• 批准号: 10454238
• 负责人: Laurie Kathleen Svoboda
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-25 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454238
• 关键词: 3-Dimensional; Action Potentials; Acute; Adult; Adult Children; Affect; Animal Model; Antioxidants; Area; Attention; Behavioral; Bioinformatics; Cardiac; Cardiac Myocytes; Cardiac development; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cells; Cessation of life; Clinical; Coupled; Cues; DNA Methylation; Data; Development; Dose; Environmental Exposure; Environmental Health; Environmental Pollution; Epigenetic Process; Equilibrium; Etiology; Exhibits; Female; Fluorescence; Functional disorder; Gene Expression; Glutathione; Goals; Heart; Heart Diseases; Heavy Metals; Heritability; Human; Incidence; Intervention; Lactation; Lead; Life; Link; Liquid Chromatography; Mass Spectrum Analysis; Measures; Mediator of activation protein; Mentored Research Scientist Development Award; Metabolic; Metabolic Pathway; Metabolism; Mitotic; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Nutritional; Optics; Outcome; Oxidation-Reduction; Pathogenesis; Patients; Perinatal; Pharmacology; Play; Predisposition; Pregnancy; Process; Prognosis; Protocols documentation; Public Health; Reactive Oxygen Species; Reduced Glutathione; Research; Research Personnel; Role; Sex Differences; Source; Testing; Toxicant exposure; Training; United States; base; building materials; cancer cell; cardiovascular disorder risk; cardiovascular effects; cardiovascular health; career; design; disability; drinking water; heart cell; heart function; human model; induced pluripotent stem cell; lead exposure; male; mortality; mouse model; novel; offspring; oxidation; programs; self assembly; sex; stem cell biology; stem cell differentiation; stem cell model; stem cells; toxicant; transcriptome sequencing; urban area

Abstract: Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality world-wide, and there are significant sex differences in their incidence, pathophysiology, and prognosis. Accumulating evidence suggests an important role for early-life toxicant exposures in the etiology of CVDs; however, the molecular mechanisms underlying these associations are unclear. In particular, the role for sex as a determinant of susceptibility to toxicant-induced cardiovascular health effects remains poorly understood. Pb exposure continues to pose a significant public health concern, particularly in poor urban areas. Perinatal and adult exposure to Pb are associated with adverse cardiovascular effects in human and animal models. One important mechanism by which early Pb exposure may influence the long-term risk of CVDs is through disruption of the precise epigenetic programs governing normal cardiac development. Recent studies in cancer and stem cell biology demonstrate that epigenetic changes and cellular differentiation are closely coupled to the metabolic state of the cell, enabling cells to detect, and rapidly respond to, environmental cues. Notably, stem cells from male and female donors exhibit intrinsic differences in differentiation programs, as well as differential sensitivity to toxicant exposures. Despite known impacts of Pb exposure on heart function, the effects of developmental Pb exposure on epigenetic and metabolic programming during cardiac development, and potential sex differences in these effects, have not been investigated. Using an established mouse model of perinatal environmental exposures, we have recently discovered that developmental Pb exposure leads to sex-specific changes in DNA methylation in the hearts of adult offspring mice. We have further discovered that hearts of Pb-exposed mice exhibit a significant increase in the oxidation of glutathione, a cellular antioxidant and metabolite that is closely coupled to epigenetic programming and stem cell differentiation. These results suggest that perinatal Pb exposure may disrupt normal metabolic and epigenetic programming in the heart in a sex-specific manner. Using human patient-derived induced pluriopotent stem cells (iPSCs) from male and female donors, the goal of this proposal is to elucidate the precise molecular mechanisms underlying Pb-induced programming on human cardiac differentiation and function, and to understand how sex differences may influence susceptibility to this toxicant. Preliminary studies in human iPSC-derived cardiomyocytes demonstrate that acute Pb exposure promotes a dose-dependent increase in action potential duration, suggesting that Pb may have arrhythmogenic effects, and demonstrating the utility of this model to assess Pb-induced effects on cardiac function. The training and research outlined in this K01 proposal will provide an outstanding framework for the development of a successful R01 application and an impactful career as an independent investigator in this understudied area of environmental health.

抽象的： 心血管疾病（CVD）是全世界发病率和死亡率的主要原因， 其发病率、病理生理学和预后存在显着的性别差异。越来越多的证据表明 生命早期有毒物暴露在 CVD 病因学中发挥着重要作用；然而，分子机制 这些关联的背后尚不清楚。特别是，性别作为易感性决定因素的作用 毒物引起的心血管健康影响仍知之甚少。铅暴露继续造成 重大公共卫生问题，特别是在贫困城市地区。围产期和成人接触铅的情况 与人类和动物模型中的不良心血管影响有关。一项重要机制是 早期接触铅可能会影响 CVD 的长期风险，原因是破坏了精确的 控制正常心脏发育的表观遗传程序。癌症和干细胞生物学的最新研究 证明表观遗传变化和细胞分化与代谢状态密切相关 细胞，使细胞能够检测环境线索并快速做出反应。值得注意的是，来自男性的干细胞 和女性捐赠者在分化计划方面表现出内在差异，以及对 有毒物质暴露。尽管已知铅暴露对心脏功能有影响，但铅对发育的影响 心脏发育过程中表观遗传和代谢编程的暴露以及潜在的性别差异 对于这些影响，还没有进行过调查。使用已建立的围产期环境小鼠模型 暴露，我们最近发现发育阶段的铅暴露会导致性别特异性的变化 成年小鼠子代心脏中的 DNA 甲基化。我们进一步发现，暴露于铅的心脏 小鼠表现出谷胱甘肽氧化显着增加，谷胱甘肽是一种细胞抗氧化剂和代谢物， 与表观遗传编程和干细胞分化密切相关。这些结果表明围产期 铅暴露可能会以性别特异性的方式破坏心脏中的正常代谢和表观遗传编程。 使用来自男性和女性捐赠者的人类患者诱导多能干细胞 (iPSC)，目标是 该提案旨在阐明铅诱导人类编程的精确分子机制 心脏分化和功能，并了解性别差异如何影响对此的易感性 毒物。对人 iPSC 衍生心肌细胞的初步研究表明，急性铅暴露 促进动作电位持续时间的剂量依赖性增加，表明 Pb 可能具有 致心律失常效应，并证明该模型可用于评估铅对心脏的影响 功能。 K01 提案中概述的培训和研究将为 开发成功的 R01 应用程序并作为独立调查员拥有有影响力的职业生涯 环境健康的研究领域。